Abstract Alzheimer's disease (AD), one of the most dreaded neurodegenerative disorders that affects 10% of all people over 65 years of age, is characterized by cortical and cerebrovascular A2 deposits, neurofibrillary tangles, chronic inflammation, and neuronal loss. Osteoporosis, another multifactoral disorder, is characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue. Both AD and osteoporosis are common chronic degenerative disorders strongly associated with advanced age. Both disorders are characterized by progressive tissue loss and are largely seen as completely independent diseases with different local restrictions of pathology. Both disorders are multifactoral mostly polygenetic diseases, involving susceptibility genes, ageing, and environmental factors as pathogenic mechanisms. Both disorders involve chronic inflammatory processes and hormonal deficiencies that play important pathogenic roles. Though not referred to as one of the major complications of AD, osteoporosis and increased bone fracture rates are commonly observed in patients with AD. Increasing evidence from clinical and epidemiological studies supports a degree of comorbidity of both disorders. However, very few studies are available in the literature that has addressed mechanisms underlying this problem, which is a long term goal of our research. Amyloid 2-peptide (A2), a major component of amyloid plaques in the brain of AD, is derived from proteolytic processing of APP (amyloid precursor protein) by secretase activities. Increased A2 production is believed to be a major cause of AD. AP, a transmembrane protein, is expressed not only in the brain/neurons, but also in many non- neuronal cells, including osteoblasts (OBs), osteoclasts (OCs), and bone marrow macrophages (BMMs). However, the function of APP and/or A2 in bone remodeling remains largely unclear, which is a major focus of our study. Our pilot studies have provided evidence for the involvement of APP and Abeta in bone remodeling. This application has the goal of determining whether APP/A2, via its receptor RAGE (receptor for advanced glycation endproduct), is a critical factor in regulating bone remodeling in an age dependent manner. The results from this proposal will provide a link between the APP-A2-RAGE axis and AD-associated bone loss, identify a new biological function of APP and A2, and reveal a new mechanism underlying OC and OB differentiation, function, and their coupling. PUBLIC HEALTH RELEVANCE: This proposal is to investigate functions of APP (amyloid precursor protein) and A2 (a cleavage product of APP with 40-42 amino acids) in regulating bone remodeling at both pathological and physiological conditions. It is relevant to our understanding of the pathogenesis of osteoporosis and Alzheimer's disorders (AD). AD, the most common cause of dementia, affects as many as 5 million Americans, and many of them are veterans. Osteoporosis, another chronic degenerative disorder, affects many aged people including veterans. Both disorders severely affect quality of life of aged veterans, but there is lack of cure treatment. It is our hope that the proposed research will provide useful information for our understanding of the pathogenesis of both disorders, which are highly relevant to the Research Objectives of VA.